PROJECT SUMMARY/ ABSTRACT Individuals receiving maintenance hemodialysis (HD) have exceedingly high mortality, driven largely by cardiovascular events. The rate of sudden cardiac death (SCD) in the HD population exceeds that of the general population by more than 20-fold. Risk factors for SCD such as structural heart disease and conduction abnormalities are common among people with end-stage kidney disease, but traditional preventive strategies, such as antiarrhythmic medications and implantable cardioverter defibrillators, do not lower SCD risk in HD patients. However, medication-provoked SCD may be preventable, and, to-date, has been understudied in HD patients. Dialysis patients are often prescribed medications that have the undesirable, off-target effect of delayed ventricular repolarization, which manifests as QT-interval prolongation on an electrocardiogram, and can trigger fatal arrhythmias. Although more than 50% of dialysis patients are prescribed medications that can prolong the QT-interval (e.g. certain antidepressants, antibiotics, antiemetics), there are critical knowledge gaps about the cardiac safety of these medications. In fact, their safety profiles rest on data obtained from healthy volunteers and have not been explicitly evaluated in HD patients. By executing the proposed studies, we will provide a comprehensive understanding of the essential safety data relevant to the prescription of non- cardiac QT-prolonging medications to HD patients. In Aim 1, we will determine the relative SCD risk of the most commonly prescribed non-cardiac medications with higher QT-prolonging potential vs. clinically relevant comparator medications with lower QT-prolonging potential among HD patients. In Aim 2, we will identify modifiable clinical factors (e.g. dialysate composition and concurrent prescription medications) that may be targeted to mitigate SCD risk from QT-prolonging medications. In Aim 3, we will identify prescribers of higher risk QT-prolonging medications and associated encounters that should prompt medication reconciliation and decision support tool use. Then, in Aim 4, we will develop individualized decision support tools for QT- prolonging medication prescribing that integrate many comorbid conditions, HD treatment, and medication- related risk factors. This work will yield decision support tools that facilitate personalized SCD risk assessments and safer prescribing of QT-prolonging medications to reduce SCD risk among HD patients. Moreover, the decision support tools generated in this project will serve as the subject of future pragmatic trials testing the impact of tool implementation on cardiovascular outcomes.